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Development of a mechanism and an accurate and simple mathematicalmodel for the description of drug release: Application to a relevant exampleof acetazolamide-controlled release from a bio-inspired elastin-based hydrogel
A. Fernandez-Colino, J.M. Bermudez, F.J. Arias, D. Quinteros, E. Gonzo
PII: S0928-4931(15)30661-5DOI: doi: 10.1016/j.msec.2015.12.050Reference: MSC 6043
To appear in: Materials Science & Engineering C
Received date: 21 July 2015Revised date: 4 December 2015Accepted date: 22 December 2015
Please cite this article as: A. Fernandez-Colino, J.M. Bermudez, F.J. Arias, D. Quinteros,E. Gonzo, Development of a mechanism and an accurate and simple mathematical modelfor the description of drug release: Application to a relevant example of acetazolamide-controlled release from a bio-inspired elastin-based hydrogel, Materials Science & Engi-neering C (2015), doi: 10.1016/j.msec.2015.12.050
This is a PDF file of an unedited manuscript that has been accepted for publication.As a service to our customers we are providing this early version of the manuscript.The manuscript will undergo copyediting, typesetting, and review of the resulting proofbefore it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers thatapply to the journal pertain.
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DEVELOPMENT OF A MECHANISM AND AN ACCURATE AND SIMPLE
MATHEMATICAL MODEL FOR THE DESCRIPTION OF DRUG RELEASE:
APPLICATION TO A RELEVANT EXAMPLE OF ACETAZOLAMIDE-CONTROLLED
RELEASE FROM A BIO-INSPIRED ELASTIN-BASED HYDROGEL
A. Fernández-Colinoa, J.M. Bermudez
b*, F.J. Arias
a, D. Quinteros
c and E. Gonzo
b,
a Bioforge Research Group, Universidad de Valladolid, CIBER-BBN, Paseo de Belén 19, 47011
Valladolid, Spain
b Facultad de Ingeniería, Instituto de Investigaciones para la Industria Química (INIQUI-CONICET),
Universidad Nacional de Salta, Av. Bolivia 5150, A4408FVY Salta Capital, Argentina
c UNITEFA – CONICET. Departamento de Farmacia. Facultad de Ciencias Químicas. Universidad
Nacional de Córdoba, 5000 Córdoba, Argentina
E-mail address: [email protected], [email protected] (J.M. Bermudez).
ABSTRACT
Transversality between mathematical modeling, pharmacology, and materials science is essential in
order to achieve controlled-release systems with advanced properties. In this regard, the area of
biomaterials provides a platform for the development of depots that are able to achieve controlled
release of a drug, whereas pharmacology strives to find new therapeutic molecules and mathematical
models have a connecting function, providing a rational understanding by modeling the parameters
that influence the release observed. Herein we present a mechanism which, based on reasonable
assumptions, explains the experimental data obtained very well. In addition, we have developed a
simple and accurate “lumped” kinetics model to correctly fit the experimentally observed drug-
release behavior. This lumped model allows us to have simple analytic solutions for the mass and
rate of drug release as a function of time without limitations of time or mass of drug released,
which represents an important step-forward in the area of in vitro drug delivery when
compared to the current state of the art in mathematical modeling. As an example, we applied
the mechanism and model to the release data for acetazolamide from a recombinant polymer. Both
materials were selected because of a need to develop a suitable ophthalmic formulation for the
treatment of glaucoma. The in vitro release model proposed herein provides a valuable predictive
tool for ensuring product performance and batch-to-batch reproducibility, thus paving the way for the
development of further pharmaceutical devices.
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Keywords: Mathematical model; Polymeric drug delivery systems; Hydrogels; Controlled
release/delivery; Biomaterials.
1. INTRODUCTION
In the pharmaceutical industry, it is essential to understand the mass-transport mechanism involved
in drug release and be able to quantitatively predict the kinetics of this process in order to
successfully design new advanced delivery systems. In this regard, suitable mathematical models
allow the effect of system-design parameters on drug-release kinetics to be estimated [1].
Accordingly, a great deal of research effort has been dedicated to the development of appropriate in
vitro release models that can provide a predictive tool for ensuring product performance and batch-
to-batch reproducibility [2] [3] [4] [5]. It is also crucial to have a good understanding of drug-release
kinetics in vivo to ensure effective and predictable product performance. However, in the early
formulation-design stages, it is not practical to test each formulation in vivo due to the time required,
expense and animal lives that this would involve.
In vitro release methods should be easy to apply and, ideally, should be predictive of in vivo release.
Thus, if an in vivo / in vitro correlation (IVIVC) can be established, then the in vitro release profile
obtained for different batches can be used to ensure product behavior in vivo for both quality-control
purposes and bioequivalence studies [6].
In general, several factors intervene in the process of drug release from the hydrogel: 1) the solubility
of the drug in the hydrogel, 2) diffusion of the drug through the membrane, and 3) the interface for
transport to the receptor solution. Although several complex models (drug dissolution, diffusion and
transfer to the fluid medium) have been applied to describe drug delivery from a hydrogel via a
membrane to a receptor solution, the mathematical complexity of these models makes them
inconvenient for practical use. As was pointed out nearly 40 years ago by Aris (1966) [7], and more
recently by Levenspiel (2002) [8], what is really needed are simple models that can provide a good
description of the system behavior.
In light of the above, the aim of this contribution is to present a mechanism based on physically
acceptable assumptions taking into account the characteristics of the experimental procedure used. In
addition, we establish an accurate, robust and easy to apply mathematical model for the description
of drug release from polymeric devices. Furthermore, as a proof of concept, we apply both (the
mechanism and the model) to an illustrative example, namely the release behavior of acetazolamide
(AZM) from a recombinant protein polymer-based hydrogel, in this case a tetrablock [9] [10]. This
tetrablock polymer belongs to a family of bioinspired protein-based polymers known as “elastin-like
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recombinamers” (ELRs) [11] [12] and displays a set of features which have motivated its utilization
as an example for applying the kinetic model developed herein. First of all, due to its recombinant
nature, it is absolutely monodisperse, thus implying a greater robustness of the release data obtained
as they will never be affected by this variable. Secondly, the similarity between the tetrablock
recombinamer and natural elastin in terms of amino acid sequence results in a similarity in other
properties, such as its biocompatibility and its inverse temperature transition behavior (ITT) [13]
[14], a concept similar to the LCST (lower critical solution temperature) notion commonly used in
chemistry-related fields. Thus, the tetrablock chains remain soluble below a characteristic
temperature known as the transition temperature (Tt) and assemble hydrophobically above this Tt,
resulting in the formation of a hydrogel. Such thermo-gelling behavior in response to
physiologically relevant stimuli, together with its biocompatibility, have positioned this
recombinamer as a potential candidate for drug-delivery purposes, especially when injectable or
topical administration is required. Thus, the tetrablock hydrogel can be applied either topically or
injected to form a gel in a matter of seconds upon sensing body temperature. Although this tetrablock
recombinamer has been physically characterized previously, its use in the field of drug delivery has
not been explored yet. Herein we study the ability of this system to deliver AZM in a prolonged
manner. AZM is a carbonic anhydrase inhibitor with weak diuretic activity and is used mainly in the
management of glaucoma [15]. Other indications include epilepsy and high-altitude disorders. By
inhibiting carbonic anhydrase in the eye, AZM decreases the formation of aqueous humor and
therefore decreases intra-ocular pressure. It is used in the preoperative management of angle-closure
glaucoma, or as an adjunct in the treatment of open-angle glaucoma. Topical administration is the
most preferred route for ophthalmic medications due to enhanced patient comfort and minimization
of potential systemic side-effects. However, this route has some limitations, such as the short
precorneal residence time and poor bioavailability of most eye-drop solutions [16]. Several
approaches to increase the ocular bioavailability of ophthalmic formulations have been investigated,
with many of them exploring the inclusion of viscosifying agents in the formulation to achieve a
lengthening of the pre-corneal contact time [17] [18].
During the design stage of these and other formulations, or during experimental verification of their
release behavior, it is desirable to develop and use simple but accurate mathematical models to
describe the release kinetics [19]. Although these models are clearly based on transport (diffusion)
equations, they are commonly known in the pharmaceutical or drug-delivery field as kinetic models,
or kinetic expressions, as they describe the time-dependent behavior of drug release. Following this
motivation, herein we present a mechanism that considers the fundamental step of diffusion in the
hydrogel matrix and mass transfer at the membrane-solution interface. Although this mechanism
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does not have an analytical solution, thus meaning that a numerical procedure must be used, it
describes the experimental data obtained very well. In addition, we have developed a kinetic model
that can ensure effective and predictable product performance, a key parameter for transfer of the
product to the pharmaceutical industry. As proof of concept, these models have been applied to a
relevant example of controlled release, namely release of AZM from a tetrablock-based depot. The
relevance of this system is based on the novel character of the tetrablock recombinamer and the need
to develop advanced therapeutic approaches for the treatment of glaucoma.
2. EXPERIMENTAL
2.1. Materials
AZM was supplied by Parafarm (Buenos Aires, Argentina) and sodium chloride by Cicarelli
Reagents (Rosario, Argentina). The tetrablock recombinamer was produced using recombinant
techniques and purified as reported elsewhere [9] [20]. Doubly distilled water was used throughout
all experiments. All chemicals were of analytical grade and were used without further purification.
2.2. Characterization of the tetrablock recombinamer
2.2.1. DSC
DSC experiments were performed using a Mettler Toledo 822e instrument with liquid-nitrogen
cooler. Both temperature and enthalpy were calibrated using a standard sample of indium. Tetrablock
samples for the DSC measurements were prepared at 15% in an aqueous saline solution (NaCl
0.9%). A volume of 20 μL of the corresponding sample was placed inside a standard 40 μL
aluminum pan and sealed hermetically.
The heating program for DSC measurements included an initial isothermal step (5 min at 0 °C to
stabilize the temperature and state of the tetrablock), followed by heating from 0 °C to 60 °C at 5
°C/min.
2.2.2. Rheology tests
The mechanical properties of the hydrogels were determined using rheological tests in a controlled
stress rheometer (AR2000ex, TA Instruments) equipped with a Peltier plate temperature control. A
parallel plate geometry with a diameter of 20 mm and a sample volume of 350 μL in aqueous saline
medium (NaCl 0.9%) was used, at a recombinamer concentration of 15 wt.%. Such concentration
was chosen in base of previous work, in which it was established 15wt. % as a suitable
concentration to achieve gel formation [9]. Temperature ramp experiments were performed by
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heating the sample from 5 to 37 °C at a rate of 2.5 °C/min, at a constant strain of 0.5% and a
frequency of 10 Hz.
2.2.3. Preparation of AZM-containing hydrogel
The liquid-like state of the tetrablock aqueous solution below its Tt makes mixing with the
therapeutic agent efficient and extremely simple. Thus, the recombinamer was mixed at 15 wt. %
with a 0.4 mg/mL solution of AZM in NaCl 0.9%. The resulting solution was kept at 4 °C overnight
to allow complete dissolution of the elastomeric recombinamer.
2.2.4. In vitro release experiments
Release experiments were performed using the membrane model. Briefly, the solution was deposited
into the release cell and maintained at 37 °C for 10 minutes to ensure hydrogel formation. Thereafter,
a dialysis membrane with a cut-off of 10 kDa was placed between the hydrogel and the compartment
of the receptor solution to avoid dissolution of the physical hydrogel. The delivery medium was
added and, at predetermined time intervals, the solution (NaCl 0.9%) was completely removed from
this compartment and new solution added. This study was conducted over 6 days.
The concentration of AZM in the release medium was determined by UV spectrophotometry at a
maximum absorbance wavelength of 265 nm (UV2 Spectrometer Unicam, New York). All
experiments were performed in triplicate.
To detect possible effects of the membrane on the release profile (drug-delivery rate), the
compartment destined to be loaded with the hydrogel was loaded with a 0.4 mg/mL solution of AZM
(without the hydrogel) and the release profile monitored as described previously.
The results were expressed as fraction of AZM released. The AZM release profile was analyzed
considering the mechanism and using the lumped kinetics model developed in this paper.
3. RESULTS AND DISCUSSION
3.1. Mathematical development of the model
Upon administration, gel-forming solutions initially undergo a transient and dynamic gelation phase
during which marked changes in their transport properties can occur over short length and time
scales. Moreover, drug release may subsequently be substantially affected by surface or bulk erosion.
From a mathematical modeling point of view, controlled-release systems may be classified as
diffusion-, chemically- or swelling-controlled processes [21]. One of the most widely used diffusion
models is that based on the Higuchi equation [22], which was generalized by the model described by
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the Ritger-Peppas equation [23]. Unfortunately, these models have the drawback that they describe
only part of the drug-release profile and are based on very restrictive assumptions.
The mechanism proposed by us to allow the entire drug-release profile to be accurately predicted is
based on the moving boundary model, which considers that the transport steps of diffusion in the
device and transport via the interface are faster than the advance of the front in the matrix. As such, a
pseudo-steady state can be applied to the transfer steps.
Others important assumptions in our mechanism are:
a) Slab geometry of the device used.
b) Uniform drug concentration throughout the device at t = 0.
c) The drug diffuses in the matrix according to Fick’s law.
d) A constant diffusion coefficient of the drug in the device matrix as a function of time.
e) Negligible transport resistance in the dialysis membrane.
Based on these assumptions, the pseudo-steady state for the transport step is given by (see Figure 1):
sso CkcA
x
CCDA **
)(*
(1)
where D is the diffusion coefficient, kc is the interface mass-transfer coefficient and A the interface
surface area. Co, Cs and Cf are the drug concentration in the device matrix, at the interface and in the
bulk receptor solution, respectively.
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Figure 1: Drug-concentration profile at t > 0.
According to the experimental setup and procedure used, Cf is always zero (fresh receptor solution is
added at each predetermined interval) and increases by a differential amount (sufficient to be
detected and measured).
Equation (1) leads to:
D
xkcC
CC
o
ssp *
1
1
(2)
and advance of the front is given by the differential equation:
so CAkcdt
dxAC **** (3)
Taking into account equation (2), the rate of advance of the front is:
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D
xkc
kc
dt
dx
*1
(4)
The mass balance for the cumulative amount of drug released at time t is given by:
sf
CkcVL
A
dt
dC* (5)
where VL is the volume of receptor solution added each time that a sample is taken.
The following equation is obtained upon dividing equation (5) by Co:
spo
f
fpCkc
VL
A
dt
C
Cd
dt
dC* (6)
where Cfp is the fraction of the cumulative amount of drug released at time t with respect to the initial
amount in the device.
The set of differential equations (4) and (6), and the analytical relationship (2), was solved
numerically using the program Polymath 6.1.
The initial boundary conditions are:
t = 0 Cs = Co (Csp = 1) x = 0
with: VL = 2 cm3 and A = 0.636 cm
2
The only transfer step involved at the beginning of the process (t = 0) is that corresponding to
interface mass transfer. As such, the value of the mass transfer coefficient can be estimated from (see
equation (5)):
0 t
fp
dt
dC
A
VLkc (7)
Polymath 6.1 gave an excellent fit with the experimental data obtained (see Figure 4). Moreover, this
agreement was found with physically reasonable values for the mass-transfer coefficient at the
interface of kc = 5.7 10-5
cm/s and a diffusion coefficient of D = 7.2 10-6
cm2/s. The value of kc is
very close to that estimated using equation (7).
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Although the mechanistic theory based on real phenomena and physically realistic assumptions
allows the fundamental coefficients that offer a great insight into the drug-release process to be
determined, a numerical procedure must be used to obtain the mass and rate of drug release at any
given time. Consequently, we proposed a lumped kinetic model that accounts for the different steps
encountered in this process and provides simple and explicit analytical solutions.
A pseudo-second-order equation model has been tested and a lumped kinetics model was found to be
suitable for this case [24].
Pseudo-second-order kinetics equation was found to consider all the transport and diffusion
steps involved in drug release processes, besides compiling with the reported need of
developing models as simple as possible to provide a good description of the system behavior
[7] [8].
The pseudo-second-order kinetic expression for the process, in this case the drug-release rate, is:
22 )( t
t MMkdt
dM (8)
Normalizing respect to M gives:
2
2 )1(* tp
t
tpMMk
dt
M
Md
dt
dM
(9)
where Mt and M are the cumulative amount of drug released at time t and at infinite time (amount of
drug feasible to be release), respectively. The amount of drug remaining in the hydrogel is given by
(M - Mt).
Considering
2* kMk (10)
Equation (9) becomes:
2)1( tptp
Mkdt
dM (11)
where Mtp is the cumulative fraction of drug released at time t, and k the kinetic parameter in time-1
.
This equation is dimensionless with respect to the amount of drug released, whereas the kinetic
parameter k depends on the amount of drug dosed in the hydrogel (M).
Solving equation (11) with conditions:
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At t = 0 Mtp = 0 and at t = t Mtp = Mtp
Gives Equation (12):
]*1[
*
tk
tkM tp
(12)
Equation (12) can be written in a more general form to fit the experimental results thus:
]*1[
*
tb
taM tp
(13)
Equation (13) can be used to determine the time needed to release a given fraction of the drug:
tp
tp
Mba
Mt
* (14)
as well as the rate of drug release as a function of time:
2)*1( tb
a
dt
dM tp
(15)
Equation (13) can be also put in linear form as:
ta
b
aM
t
tp
*1 (16)
Using equation (16) and plotting a graph of (t / Mtp) versus time (t) gives a first estimate of the values
of parameters “a” and “b”.
This lumped model considers the different mass transport steps involved in drug release
system. The model can be applied without limitations of time or mass of drug released. That is,
it can be applied to fit the experimental data in the range 0 ≤ t ≤ ∞ or 0 ≤ Mt ≤ M∞.
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Furthermore, analysis using our proposed approach, yielded simple and explicit relations
between mass and drug released rate with time.
3.2. Testing use of the tetrablock as a delivery vehicle for AZM
3.2.1. Thermo-gelling properties of the tetrablock-AZM device
The thermo-gelling properties of the tetrablock alone and in combination with AZM in saline
solution (NaCl 0.9%) were evaluated in order to determine whether the presence of the drug in the
tetrablock sample affects its thermo-gelling behavior. To this end, the corresponding samples were
subjected to rheological tests comprising heating from 5 to 37 °C at a constant rate of 2.5 °C/min,
and the parameters G' and G'' were collected. G´ (also named as storage modulus or elastic
modulus) is a measure of the ability of the material to store energy. In other words, it is a
measure of elasticity of material. G'' (also named as loss modulus or viscous modulus) is a
measure of the ability of the material to dissipate energy during the shearing process.
As shown in Figure 2 a) and d), a sharp increase in G' and G'' occurs for both samples in the
temperature range 12–18 °C. Specifically, the crossover between G' and G'', which is the most
commonly used criterion for determining the gel point [25], occurs at 15.5 °C for both samples
(tetrablock and tetrablock with AZM). At such point, the storage modulus becomes larger than
the loss modulus which indicates that the fluid has transitioned from fluid flow like behavior to
solid elastic behavior.
DSC scans were performed to confirm the absence of any influence of AZM on the ITT behavior of
the tetrablock. As shown in Figure 2c) and Figure 2d), no difference between ITT variables, namely
temperature (12.5 °C), and enthalpy (8.8 J/g) were found, thereby supporting the lack of interference
between the drug and the recombinamer. Consequently, it was concluded that the presence of AZM
in the hydrogel does not affect the thermo-gelling properties of the system. These findings point to
the potential utility of the tetrablock recombinamer as a vehicle for achieving controlled AZM
release. The liquid-to-gel transition behavior of this biomaterial potentially allows topical
administration of the formulation as drops. Upon contact with the surface of the eye, the system
would acquire a gel-like state immediately after administration, thereby enhancing the bioavailability
of AZM.
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Temperature (ºC)
0 10 20 30 40 50 60 70
Temperature (ºC)
0 10 20 30 40 50 60 70
0.2 mW 0.2 mW
Temperature (ºC)
0 10 20 30 40
G´,
G´´
(P
a)
10
100
1000
10000
G'
G''
Temperature (ºC)
0 10 20 30 40
G´,
G´´
(P
a)
10
100
1000
10000
G'
G''
a) b)
c) d)
Figure 2. Thermo-gelling properties of the tetrablock. a) Storage moduli (G') and loss moduli (G'')
for the tetrablock sample (15 wt.%) in NaCl 0.9% as a function of temperature. b) Storage moduli
(G') and loss moduli (G'') for the tetrablock sample (15 wt.%) in NaCl 0.9% with 0.4 mg/mL AZM
as a function of temperature. c) DSC scans for the tetrablock sample (15 wt.%) in NaCl 0.9%. d)
DSC scans for the tetrablock sample (15 wt.%) in NaCl 0.9% with 0.4 mg/mL AZM.
3.2.2 AZM release from the tetrablock hydrogel
3.2.2.1 Experimental data for release of AZM from the tetrablock hydrogel in vitro
Once it had been demonstrated that the thermo-gelling properties of the tetrablock under
physiological conditions were not affected by the presence of AZM, the next step was to evaluate the
ability of this device to achieve sustained release of the therapeutic agent.
To this end, in vitro release tests were performed as described in the experimental section. An initial
analysis of the release profile shows that AZM delivery is sustained over the period studied (150 h,
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approximately 6 days), with a visible absence of burst release at the initial time-points (Figure 3).
Although the absence of burst release is a requirement in order to minimize undesiderable peak
concentrations of the drug exceeding the therapeutic dosage when applied in vivo, it is often difficult
to achieve. As was expected, the release profile from the control cell (with AZM, but without
recombinamer) did not display sustained release (Figure 3, empty circles), thereby confirming the
assumption of negligible transport resistance through the dialysis membrane (section 3.1, assumption
e))
The prolonged-release profile of this system, together with the absence of burst release, suggests the
potential application of this formulation in the area of ophthalmic formulations.
Time (h)
0 20 40 60 80 100 120 140 160
(Mt%
) T
ota
l re
leas
e
0
20
40
60
80
100
Tetrablock hydrogel
Control
Figure 3. Cumulative release of AZM from tetrablock hydrogel at 37 °C in NaCl 0.9% (black
circles). The empty circles correspond to the negative control, which comprised placing an AZM
solution in the release cell in the absence of hydrogel.
3.2.2.2. Modeling of in vitro AZM release from the tetrablock hydrogel
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A multidisciplinary approach must be followed when designing a pharmaceutical formulation in
order to both develop the polymer and the therapeutic agent and to take into account appropriate
mathematical modeling. Such modeling must be able to correctly describe the system and predict the
effects of different parameters on the release profile, and ultimately constitutes a key link in the
development of pharmaceutical devices.
Considering the experimental procedure used, it is important to point out that the time period
between two consecutive samples should be sufficient to accurately measure the change in Mtp but
small enough to consider dMtp/dt (Mtp/t). Under this condition, equation (15) will give us the
maximum rate of drug delivered (time-1
) when the amount of drug remaining in the hydrogel is (M -
Mt).
In order to calculate the fraction of drug released and the release rate at any particular time, equations
(13) and (15) can be applied to the whole range of Mtp (0 (Mtp) ≤ 1).
Time (h)
0 20 40 60 80 100 120 140 160 180
Mtp
or
Cfp
0.0
0.2
0.4
0.6
0.8
1.0
Experimental
Mechanism
Model
Figure 4. Fraction of AZM released (Mtp). Squares: experimental data. Triangles: predicted values
of AZM release from tetrablock hydrogel (Mtp) obtained by applying the non-linear regression
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resolution of the model developed in this contribution using the Polymath program. Circles:
predicted values of AZM released from tetrablock hydrogel (Cfp) obtained by solving the
mechanism proposed.
The best procedure for obtaining the values of “a” and “b” is to carry out a non-linear regression
analysis of the experimental data with the model presented herein using the values of “a” and “b”
determined from the plot of equation (16) as a first estimate. A non-linear regression analysis with
Polymath 6.1 gave the following values for the parameters “a” and “b”:
1018381.0 ha and 015014.0b h-1
with 9900.02 R
Therefore, the percentage amount of drug delivered as a function of time is given by (equation (13)):
]*015014.01[
*018381.0)(
t
tM tp
(17)
The values of (Mtp) as a function of time (t) estimated using the parameter values given by the non-
linear regression analysis are plotted in Figure 4.
Thus, the drug-release rate [d(Mtp)/dt] as a function of time, according to the parameter values
obtained by non-linear regression analysis and using equation (15), is:
2]*015014.01[
018381.0)(
tdt
Md tp
(18)
As can be seen, the ratio between parameters a and b is close to one, thereby supporting the
experimental results, the internal consistency of the experimental methodology, and the suitability of
the proposed model for fitting the results.
The main advantage of our model is that the solution of the kinetic gives a simple equation as
function of time that lumped the different steps involved in the process, which is valid for 0≤ t
≤ ∞ where 0 ≤ Mt ≤ M∞. Also, the drug release rate can be easy found for any value of time
(t= 0 to t=∞) , which is not possible to do with the Ritger-Peppas model because it cannot be
applied to calculate the initial release rate neither to obtain M∞ [26] [27]. Note that our model is
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equivalent to the Ritger-Peppas model equation, but with a value of parameter “n” changing
continuously from one at the beginning of the process to near zero at long time.
The reason for the increasing need to develop novel options for drug delivery to the eye is based on
the need to progress from drug delivery discovered in earlier research into topically administered
drugs. Although pharmaceutical research and development provides a route to achieve this objective,
it is sometimes limited by available technology and regulatory constraints. The cost of the finished
product must be bearable by the individuals and/or communities who will use the product, and it has
to be economically viable for the manufacturer. The development of mathematical models that are
able to accurately predict drug-release behavior constitutes a must in this context.
4. CONCLUSIONS
The development of mathematical models that are able to accurately predict drug-delivery profiles is
a critical step in pharmaceutical product development. Herein we have presented a drug-release
mechanism based on the moving-boundary model that is appropriate for the experimental procedure
used. The mechanism takes into account drug diffusion in the hydrogel and transfer at the device-
fluid interface. The shape of the complete release profile (up to 83% drug delivered) was modelled,
giving an excellent fit with physically reasonable values for the diffusion and interface mass transfer
coefficients. However, as a numerical method must be applied to solve the mechanism, it is not
possible to derive explicit analytical solutions. We have also developed a second-order kinetic
“lumped model” for the rate of drug release, and explicit analytical solutions for the fraction of drug
release and rate of drug release as a function of time have been obtained. Although these equations
fit the experimental data reasonably well, they are very simple and explicit analytical expressions
that can be used to rapidly analyze experimental drug-release data to get a rough idea of the possible
release mechanism. Furthermore, a simple internal consistency proof of the model and the
experimental results has been developed using the ratio of parameters “a” and “b”. Note that no
limitations of time or of mass of drug released are required to apply the “lumped model”. As
such, complete drug delivery profile can be fitted, which represents an important achievement
in the area of mathematical modeling.
As proof of concept, we have applied this model to a relevant experimental example in which release
of AZM from a tetrablock hydrogel was evaluated. This tetrablock hydrogel represents a versatile
and innovative system for the sustained local delivery of AZM, the duration of which lasted from
hours to days. As such, the tetrablock hydrogel can offer better control of local drug levels, and less
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frequent and more convenient administration, thus leading to greater efficacy, reduced adverse
events and better patient compliance. It can also provide advantages (e.g., efficiency and cost
savings) to the provider and the health care system. The mechanism and second order drug release
lumped kinetics model developed in this contribution fit the experimental data over the whole range
of fraction of drug release (0 Mtp 1) very well, thus allowing us to be able to accurately predict
the maximum drug-release rate at each time point due to the experimental procedure used. The
encouraging results presented in this work pave the way for use of these novel platforms in the
treatment of open-angle glaucoma and provide an accurate, robust and easy-to-apply mathematical
model for the description of drug release from polymeric devices.
ACKNOWLEDGMENTS
The authors acknowledge financial support from the EU via the European Social Fund (FSE), the
Operative program of Castilla y León, and the JCyL, via the Consejería de Educación, the European
regional development fund (ERDF), MINECO (MAT2013-41723-R, MAT2013-42473-R,
PRI−PIBAR-2011-1403, and MAT2012-38043), the JCyL (Projects VA155A12, VA152A12, and
VA244U13), CIBER-BBN, and the Instituto de Salud Carlos III under the Network Center of
Regenerative Medicine and Cellular Therapy of Castilla and Leon. The authors would also like to
thank CONICET (Argentina) for research fellowships, CIUNSa (Grant PROY C N° 2199/0),
CONICET (PIP 11220120100313CO), ANPCyT (PICT 2012 – 2643) and ANPCyT-MICINN
(Argentina-Spain) (PICT 2011-2751).
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Graphical abstract
Highlights
Engineering approaches, novel in the pharmaceutical field, were applied.
We have presented a drug-release mechanism based on the moving-boundary model.
The "lumped kinetic model" provides simple and explicit analytical solutions.
The tetrablock hydrogel can offer better control of local acetazolamide levels.
We developed novel platforms for the treatment of open-angle glaucoma.